New drugs for malaria that target histone deacetylases. There is no vaccine for malaria and current drugs are failing, contributing to millions of malaria-related deaths each year. The aim of this project is to develop new drugs to address this significant global health issue. This project will focus on drugs that act in novel ways to existing malaria drugs by targeting enzymes that are involved in altering gene expression in the parasite. These kinds of enzymes are recognised drug targets in ot ....New drugs for malaria that target histone deacetylases. There is no vaccine for malaria and current drugs are failing, contributing to millions of malaria-related deaths each year. The aim of this project is to develop new drugs to address this significant global health issue. This project will focus on drugs that act in novel ways to existing malaria drugs by targeting enzymes that are involved in altering gene expression in the parasite. These kinds of enzymes are recognised drug targets in other diseases such as cancer. The outcomes of this project will include advances in malaria drug development that build on Australian drug discovery efforts, seeding further funding opportunities from industry and other sources and contributing research training and capacity building in Australia.Read moreRead less
Characterisation of two-pore domain potassium channels: structure-function studies of the M1-P1 loops of TASK channels. TWIK-related Acid Sensitive K+ (TASK) channels are members of the novel class of two-pore domain potassium channel family. They are potently inhibited by local anaesthetics and have been implicated as having important roles in many pathophysiological conditions such as heart arrythmias, stroke, epilepsy, breast and other cancers. The in depth structural and functional character ....Characterisation of two-pore domain potassium channels: structure-function studies of the M1-P1 loops of TASK channels. TWIK-related Acid Sensitive K+ (TASK) channels are members of the novel class of two-pore domain potassium channel family. They are potently inhibited by local anaesthetics and have been implicated as having important roles in many pathophysiological conditions such as heart arrythmias, stroke, epilepsy, breast and other cancers. The in depth structural and functional characterisation of this class of potassium channels is of great importance as they are interesting targets for new therapeutic developments. Advancement of knowledge in the structure and function of these channels will underpin drug targeting that will aid preventative healthcare, allowing Australians to age well and age productively.Read moreRead less
Investigating the mechanisms of flavonoid actions on glycine receptors. The research to be conducted in this project will use state-of-the-art electrophysiological and molecular biological approaches to carefully characterise the actions of certain flavonoid compounds on the glycine-receptor channel. These compounds have recently been reported to act as modulators of ligand-gated ion channels, proteins integral to brain function and disease. However, no-one has studied in any detail the mechan ....Investigating the mechanisms of flavonoid actions on glycine receptors. The research to be conducted in this project will use state-of-the-art electrophysiological and molecular biological approaches to carefully characterise the actions of certain flavonoid compounds on the glycine-receptor channel. These compounds have recently been reported to act as modulators of ligand-gated ion channels, proteins integral to brain function and disease. However, no-one has studied in any detail the mechanisms by which these compounds act. By discovering their site and mechanisms of action we will further our understanding of these important proteins and their modulation, maintain Australia's significant expertise in this field and provide leads for future development of drugs with potential therapeutic value.Read moreRead less
Determinants of Expression, Assembly and Function of the Noradrenaline Transporter. The noradrenaline transporter protein that is the focus of this project is important for mental health because it belongs to the family of proteins where psychostimulants, such as cocaine, and drugs used in the treatment of depression act. The project will lead to exciting advances in our understanding of how the structure of this protein controls its functions, and potentially to the design of better antidepress ....Determinants of Expression, Assembly and Function of the Noradrenaline Transporter. The noradrenaline transporter protein that is the focus of this project is important for mental health because it belongs to the family of proteins where psychostimulants, such as cocaine, and drugs used in the treatment of depression act. The project will lead to exciting advances in our understanding of how the structure of this protein controls its functions, and potentially to the design of better antidepressant drugs and to the design of drugs to prevent the effects of cocaine.Read moreRead less
Molecular neurobiology of the GABAB receptor: Studies of heteromeric receptor function and signalling. The G protein-coupled receptor (GPCR) for the inhibitory transmitter gamma- aminobutyric acid (GABA) is a unique heterodimer. Molecular analyses will be undertaken to provide insights into its signalling mechanisms and functional regulation. Investigations employing point mutant and chimeric receptors will analyse how ligand binding to the extracellular domain of the GABA-BR1 subunit triggers ....Molecular neurobiology of the GABAB receptor: Studies of heteromeric receptor function and signalling. The G protein-coupled receptor (GPCR) for the inhibitory transmitter gamma- aminobutyric acid (GABA) is a unique heterodimer. Molecular analyses will be undertaken to provide insights into its signalling mechanisms and functional regulation. Investigations employing point mutant and chimeric receptors will analyse how ligand binding to the extracellular domain of the GABA-BR1 subunit triggers G protein-coupling to the intracellular portion of the GABA-BR2 subunit. Focus will be on different modes of GPCR signalling, including constitutive activity and roles for membrane and cytosolic regulatory proteins. Targeted studies of GABAB receptor subunits will provide new information on the mechanistic regulation of GPCR signalling.Read moreRead less
Alpha-Conotoxins: Selective Probes For Nicotinic Receptor Subtype Structure And Function. Marine snails from the waters off the Australian coast produce an amazing variety of mini-proteins in their venoms called conotoxins that they use to capture prey. These conotoxins bind very specifically to receptors in our body associated with the transmission of nerve signals. We will use natural and synthetically modified conotoxins to selectively block particular types of neuronal 'receptors' to gain a ....Alpha-Conotoxins: Selective Probes For Nicotinic Receptor Subtype Structure And Function. Marine snails from the waters off the Australian coast produce an amazing variety of mini-proteins in their venoms called conotoxins that they use to capture prey. These conotoxins bind very specifically to receptors in our body associated with the transmission of nerve signals. We will use natural and synthetically modified conotoxins to selectively block particular types of neuronal 'receptors' to gain a greater understanding of how the nervous system functions. This knowledge will help in the design of new drugs to treat a variety of diseases and disorders. Essentially we will use a chemical armoury developed by the cone snail to design state-of-the-art mini-protein drugs.Read moreRead less
Conotoxins: Novel probes for ion channel structure and function. Voltage-dependent and ligand-gated ion channels are intrinsic membrane proteins that play a central role in communication in excitable cells, particularly in the nervous system. The primary goals of this project are (i) to define at a molecular level, the structural and functional determinants of ion channel/conotoxin interactions and (ii) develop new probes that advance neurophysiological research. The diversity and distribution o ....Conotoxins: Novel probes for ion channel structure and function. Voltage-dependent and ligand-gated ion channels are intrinsic membrane proteins that play a central role in communication in excitable cells, particularly in the nervous system. The primary goals of this project are (i) to define at a molecular level, the structural and functional determinants of ion channel/conotoxin interactions and (ii) develop new probes that advance neurophysiological research. The diversity and distribution of ion channel types and subtypes being uncovered through the use of molecular biology and conotoxin probes presents an exciting opportunity for the future development of novel ion channel therapeutics.Read moreRead less
New modulators of voltage-gated sodium channel subtypes from Australian Tarantula venoms. The venoms of Australian tarantula spiders provide a unique and untapped source of bioactive molecules. From a large stock of venom, and in collaboration with Australian pharmaceutical company Xenome, we will develop a comprehensive library of venom components suitable for drug screening. Potential national benefits from this work include a huge reduction in the healthcare bill deriving from a new treatmen ....New modulators of voltage-gated sodium channel subtypes from Australian Tarantula venoms. The venoms of Australian tarantula spiders provide a unique and untapped source of bioactive molecules. From a large stock of venom, and in collaboration with Australian pharmaceutical company Xenome, we will develop a comprehensive library of venom components suitable for drug screening. Potential national benefits from this work include a huge reduction in the healthcare bill deriving from a new treatment for pain, as well as substantial royalty returns from drugs sales. Discoveries from the program are also likely to lead to an enhancement in Australia's reputation in the neurosciences and to the development of new diagnostic research tools. The major community benefit will be a reduction in the suffering of chronic pain patients.Read moreRead less
Defining mechanisms of action of novel alpha-conotoxins at nicotinic receptor-channels. Marine snails from the waters off the Australian coast produce an amazing variety of mini-proteins in their venoms called conotoxins that they use to capture prey. These conotoxins bind very specifically to receptors in our body associated with the transmission of nerve signals. We will use natural and synthetically modified conotoxins to selectively block particular types of neuronal 'receptors' to gain a gr ....Defining mechanisms of action of novel alpha-conotoxins at nicotinic receptor-channels. Marine snails from the waters off the Australian coast produce an amazing variety of mini-proteins in their venoms called conotoxins that they use to capture prey. These conotoxins bind very specifically to receptors in our body associated with the transmission of nerve signals. We will use natural and synthetically modified conotoxins to selectively block particular types of neuronal 'receptors' to gain a greater understanding of how the nervous system functions. This knowledge will help in the design of new drugs to treat a variety of diseases and disorders. Essentially we will use a chemical armoury developed by the cone snail to design state-of-the-art mini-protein drugs.Read moreRead less
Understanding and predicting small molecule binding to G protein-coupled receptors (GPCRs). The discovery of new treatments for serious diseases is a time consuming and expensive process. Our work involves developing and testing new computational modelling approaches with experimental validation for the understanding and prediction of how current and new drugs interact with their targets, and these methods can be extended for improved understanding of how other proteins work. Our approaches have ....Understanding and predicting small molecule binding to G protein-coupled receptors (GPCRs). The discovery of new treatments for serious diseases is a time consuming and expensive process. Our work involves developing and testing new computational modelling approaches with experimental validation for the understanding and prediction of how current and new drugs interact with their targets, and these methods can be extended for improved understanding of how other proteins work. Our approaches have the potential to increase the speed, reduce the cost and lead to the discovery of new treatments for serious crippling diseases such as anxiety, depression, diabetes, and obesity. Read moreRead less